Facile aromatic nucleophilic substitution (SNAr) reactions in ionic liquids: An electrophile-nucleophile dual activation by [Omim]Br for the reaction

Article abstract of DOI:10.1039/c6gc01742h

A facile aromatic nucleophilic substitution (S_NAr) reaction in recyclable [Omim]Br under relatively mild conditions has been described. An electrophile-nucleophile dual activation by [Omim]Br is also discovered based on control experiments, ¹H NMR and IR spectroscopies. This chemistry provides an efficient and metal-free approach for the generation of C_aryl-X (XS, N, O) bonds, many of which are significant synthetic intermediates or drugs, making this methodology attractive to both synthetic and medicinal chemistry.

Full text of DOI:10.1039/c6gc01742h

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PAPER
Facile aromatic nucleophilic substitution reactions (S Ar) in ionic
N
liquid: An electrophile-nucleophile dual activation by [Omim]Br
for the reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Xiao Zhang, Guo-ping Lu*, Chun Cai
DOI: 10.1039/x0xx00000x
A facile aromatic nucleophilic substitution reaction (S
N
Ar) in recyclable [Omim]Br under relatively mild conditions has been
1
www.rsc.org/
described. An electrophile-nucleophile dual activation by [Omim]Br is also discovered based on control experiments, H
NMR and IR spectroscopies. This chemistry provides an efficient and metal-free approach for the generation of Caryl-X (X =
S, N, O) bonds, many of which are significant synthetic intermediates or drugs rendering this methodology attractive to
both synthetic and medicinal chemistry.
Introduction
Recently, ionic liquids (ILs) have become tunable and
multipurpose materials for a variety of applications, such as
organic synthesis, catalysis, chemical separation, material and
energy science, due to their unique chemical or biological
1
properties. Among them, the imidazolium-based ILs that are
one of the first to find applications on an industrial scale, are
2
the most commonly investigated group for organic synthesis.
Both imidazolium-based IL cations’ H-atoms of C-2 position
and anions’ lone pairs can form hydrogen bondings (HBs) with
3
each other or other subtracts during the reactions, by which
4
some transformations can be further enhanced. Therefore,
N
Fig. 1 Working hypothesis: an electrophile-nucleophile dual activation by ILs in S Ar
the exploration of organic reactions in imidazolium-based ILs,
in which HBs between ILs and substrates are formed to
promote the reaction, is an appealing and greener alternative
to organic synthesis.
reactions.
substrates’ electrophile and nucleophile. Although most of
nitroaryl fluorides are applied in these protocols under mild
conditions and the aqueous medium can be also recycled by
simple extraction, electron-deficient fluoroarenes without
nitro group and most of electron-deficient chloroarenes fail to
provide the desired products in water.
N
Aromatic nucleophilic substitution reactions (S Ar) are one
of the powerful tools in medicine and chemical industry owing
5
to their atom economy and metal-free conditions. However, a
major drawback is that dipolar, aprotic solvents such as DMF,
6
DMAc, NMP and DMSO, are often required. These solvents
7
may cause significant health issues, meanwhile an aqueous
Similarly, imidazolium-based ILs can also form HBs with
electron-deficient aryl halides and nucleophiles, and be
recycled by simple extraction. Furthermore, they have better
solubility for substrates and higher boiling points than water,
work-up procedure for the wastewater contain these solvents
8
are also required. To resolve the issue, several attempts have
been made to use water in place of these solvents, in which
9
the use of surfactants and the formation of HBs between
which are beneficial to S Ar reactions. On the basis of these
N
1
substrates and water can accelerate the S Ar reactions
0
results, we reasoned that imidazolium-based ILs could be ideal
N
solvents for S
nucleophile dual activation is triggered to promote S
reactions (Fig. 1). To our best knowledge, there is no report on
the S Ar reactions in ILs and exploring the activation
mechanism of ILs in the transformation. Alone this line, we
describe an efficient S Ar reaction in [Omim]Br for the
N
Ar reactions, by which an electrophile-
because of high local concentrations and the improvement of
N
Ar
N
N
construction of Caryl-X (X = S, N, O) bonds, in which the
promotion of [Omim]Br on the reaction is investigated.
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Moreover, the chemistry provides several advantages
including free of metal catalysts, relatively mild conditions, the
use of recyclable solvents, high yields and broad substrate
scope that are in alignments with the principles of green
1
1
chemistry.
Results and discussion
To probe the feasibility of our working hypothesis, we started
our investigation by reacting 1-fluoro-2-nitrobenzene 1a with
4-methylbenzenethiol 2a (Table 1). After screening different
solvents, [Omim]Br proved to be the best choice for the
reaction (entry 1). Bases were also necessary for the reaction
as the acid-accepters. Although Cs
provided excellent yield of the product 3a (entries 15, 18, 19),
only K PO could afford full conversion when the amount of
base was reduced to 1.1 equiv. Only moderate yields were
afforded at lower temperatures (entry 19). Moreover, K PO
have lower toxic and cost than the other two bases.
2 3 3 4
CO , DBU and K PO
3
4
1
Fig. 2 H NMR spectra of (a) The mixing of 2a and [Omim]Br after 30 min, (b) The
mixing of 1a and [Omim]Br after 30 min, (c-e) The reaction of 1a and 2a in [Omim]Br
with K PO after 12 h (c), 1 h (d), 30 min (e). (f) [Omim]Br.
3
4
3
4
After comparing with different ILs, it was found that C-2
hydrogen of [Omim]Br might enhance the reaction by forming
certain influence on the process. A slight lower yield was
observed in [Omim]I (entries 19 vs 21) presumably owing to
the weaker hydrogen bond acceptor (HBA) (β scale)
4
HBs with substrates (entries 19 vs 20). Anions of ILs had a
a
Table 1 Optimization of reaction conditions
1
2
property. The acidic IL could inhibit the reaction since the
base was consumed by IL (entry 26). The length of alkyl groups
had no evident effect on the chemistry, but [Omim]Br
emerged as the best option owing to better flowability than
NO2
NO2
F
SH
S
+
1a
2a
3a
[
Hmim]Br and [Bmim]Br (entries 19, 25, 26).
b
Entry
Solvent
[Omim]Br
MeCN
Base
Yield (%)
Further experiments were also performed to investigate the
1
2
3
4
5
6
7
8
9
K
K
K
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
92
hypothetical interaction between [Omim]Br and substrates
1
(
52
1a,
2a). The model reaction was monitored by H NMR
(Fig. 2). Based on these results, it was
EtOH
75
spectroscopy in CDCl
3
water
29
found that the proton at the C-2 position of the imidazolium
moiety shifted from 10.233 (f) to 10.186 (30 min, e), 10.285 (1
h, d) and 10.456 (12 h, c), which could be considered as
evidences of the electrophile–nucleophile dual activation by
[Omim]Br. Firstly, the charge-charge interaction between the
quaternary N atom of [Omim]Br and the S atom of 2a and HB
THF
41
DMSO
74
DMF
65
Hexane
32
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Omim]Br
[Ommim]Br
[Omim]Cl
[Omim]I
NaOH
NEt
KOH
Na CO
t-BuOK
85
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
3
62
83
-
formation between Br and thiol S-H hydrogen can increase the
3,13
charge density of imidazole ring (nucleophilic activation), so
14
the proton shifted from 10.233 to 10.186.
2
3
64
77
.
3
NH
H
2
O
66
Then, HB is generated between the C-2 hydrogen and F
atom, resulting in an electrophilic activation of the C-F bond’s
C
S2CO
3
96
Piperidine
DABCO
DBU
88
4
,13
carbon.
Meanwhile, the charge-charge interaction of the
81
97
c
quaternary nitrogen atom and S atom decreases along with
the formation of the C-S bond in reaction. Thus, the charge
density of imidazole ring is reduced, making C-2 proton shift to
low field (10.186 to 10.285). Finally, the F atom separates from
d
e
K
K
K
K
K
K
K
K
3
PO
3
PO
3
PO
3
PO
3
PO
3
PO
3
PO
3
PO
/
4
4
4
4
4
4
4
4
>99, >99, 68, 51
f
73
98
89
1
a to be the anion of IL, which further drops the charge
[Omim]OAc
97
density of imidazole ring (10.285 to 10.456). Based on these
results, it can be concluded the electrophile-nucleophile dual
activation by [Omim]Br may be a stepwise process or a
pathway between stepwise mechanism and synergistic
[Omim]HSO
[Hmim]Br
[Bmim]Br
[Omim]Br
4
trace
96
93
trace
4
,10
mechanism unlike the previous literature.
The results of
a
o
Conditions: 1a 1.0 mmol, 2a 1.2 mmol, base 3.0 equiv, solvent 1.0 mL, 80 C, 12
interactions between IL and subtrates (1a, 2a) were also
b
c
d
o
e
f
h. GC yields,
3 4
K PO was 1.1 equiv. At 50 C. At room temperature.
[Ommim]Br was 1,2-dimethyl-3-octyl-1H-imidazol-3-ium bromide.
2
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ortho-nitroaryl fluorides could react with 2a smoothly to yield
the desired products 3a 3e. Prolonging reaction time to 24 h
-
o
or increasing temperature to 120 C were required using
nitroaryl fluorides containing electron-donating groups (EDGs)
as the starting materials (3f
with other electron-withdrawing groups (EWGs) could also
applied in the approach for longer reaction time (3h 3j 3k).
Satisfactory yields were provided at higher temperature (120
, 3g). To our delight, fluoroarenes
,
,
o
C) when electron-deficient aryl chlorides were employed (3a
,
3
e,
3h-3j), and a 77% yield of 3l was also afforded from 2-
o
fluoropyridine at 120 C for 24 h. Likewise, substituted phenyl,
heteroaryl and naphthyl thiols could react with nitroaryl
fluorides to produce the corresponding aryl sulfides (Scheme
2
,
3m
reactions of alkyl and allyl thiols and nitroaryl fluorides under
optimized conditions (3q 3r 3u 3v). Lower temperature (50
C) was demanded in the cases of benzyl thiols (3w 3x).
-3p, 3s, 3t). Good to excellent yields were provided in the
,
,
,
o
,
To further broaden the scope of the reaction, we also
focused on employing amines to the protocol (Scheme 3).
Secondary amines and benzyl amine have higher reactivity
Scheme 1 The S
N
Ar reactions of electron-deficient aryl halides with p-tolylthiol in
a,b
a
[
Omim]Br.
o
Conditions: 1 1.0 mmol, 2a 1.1 mmol, K PO 1.1 mmol, [Omim]Br 1 mL,
3
4
b
c
o
d
8
0 C, 12 h. Isolated yields. At 120 C. 24 h.
a,b
a
b
Scheme
2
N
The S Ar reactions of nitroaryl fluorides with thiols in [Omim]Br.
o
Conditions: 1 1.0 mmol, 2 1.1 mmol, K
3
4
PO 1.1 mmol, [Omim]Br 1 mL, 80 C, 12 h.
c
d
o
Isolated yields. 24 h. At 50 C.
according with our assumptions (a, b vs f). Additionally, the
reaction was examined by IR spectroscopy, and similar results
were obtained (see ESI). Clarification of the detailed
mechanism is a goal in our future research by experiments and
quantum chemical calculations.
a,b
a
Scheme 3 The S
N
Ar reactions of aryl halides with amines in [Omim]Br.
Conditions:
o
b
aryl halide 1.0 mmol, amines 1.1 mmol, K
3
PO 1.1 mmol, [Omim]Br 1 mL, 80 C, 12 h.
4
With the optimized conditions in hands, a series of electron-
c
d
e
f
Isolated yields. At rt for 6 h. At rt for 12 h. The use of 0.9 equiv of pyrrolidine. At
deficient aryl halides
1
were applied to establish the scope and
o
g
o
h
5
0 C for 24 h. At 80 C for 24 h. The use of 2.2 equiv of amines.
generality of the protocol (Scheme 1). Generally, para- or
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1
00
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
0
1
2
3
4
5
6
7
8
9
10
a,b
a
run time
Scheme 4 The S
N
Ar reactions of aryl halides with arenols in [Omim]Br
Conditions:
o
b
aryl halide 1.0 mmol, arenol 1.1 mmol, K
3
PO 1.1 mmol, [Omim]Br 1 mL, 80 C, 24 h.
4
a,b
a
Fig.
methylamino)ethanol 11 mmol, K
Isolated yields.
3
Recycle studies.
Conditions: 2-fluoropyridine 10 mmol, 2-
c
d
o
Isolated yields. 12 h. At 120 C for 18 h.
o
b
(
3 4
PO 11 mmol, [Omim]Br 10 mL, 50 C, 24 h.
To our delight, a series of arenols also provided the final
products (5a 5e) under similar conditions (Scheme 4). As
-
expected, alkyl alcohol was yielded the final product 5f. Higher
temperature was needed in the case of 4-chloroacetophenone
(
5g). To further demonstrate the potential of this
methodology, two compounds ( and ) were synthesized by
Ar reactions in [Omim]Br, which were significant
6
7
S
N
9
b
intermediates of antitumor agents (GW610 and NVP-
1
6
BKM120 ) (Scheme 5). A one-pot sequence involving an initial
Ar reaction followed by NO reduction occurred smoothly in
the case of
S
N
2
6.
Finally, investigations were also conducted to assess the
potential for recycling of the reaction medium and the
reaction of 2-fluoropyridine and 2-(methylamino)ethanol was
selected as the model reaction. Meanwhile, we scaled up the
model reaction to 10 mmol to show the possibility for large-
scale operations. After completion of reaction, the product
undergoes in-flask extraction with minimum amounts of an
organic solvent (MTBE). The phase of [Omim]Br was separated
by simple extraction and reuse for next run. The process could
be repeated 10 times without an obvious change in yields, but
the flowability of [Omim]Br was decreasing along with the
increase of inorganic salts’ amount (Fig. 3).
Scheme 5 The synthesis of drug Intermediates 6 and 7 by the S
Omim]Br
N
Ar reactions in
[
than aryl amines, so the reactions of them with fluoroarenes
could be completed at room temperature (4a, 4b 4e 4f 4h
4l). Aryl amines were also employed in the reaction
successfully (4c 4d). Notably, iminazole reacted with 4-
fluoronitrobenzene to yield the desired product 4g. The
,
,
,
,
4j-
,
Experimental section
reactions of electron-deficient aryl chlorides with amine also General remarks: All chemical reagents were obtained from
took place (4a 4b 4e 4i-4m). In the cases of 2,4,6-trichloro- commercial suppliers and used without further purification. All
pyrimidine, the selectivity between mono-substituted product known compounds were identified by appropriate technique
,
,
,
1
13
(
4j) and di-substituted one (4k) could be controlled by such as H NMR and C NMR and MS. All unknown
1
13
changing the amount of amines. However, a 15% yield of 2- compounds were characterized by H NMR, C NMR, MS and
substituted product 4j’ was produced. Moreover, 2- elemental analyses. Analytical thin-layer chromatography was
o
fluoropyridine worked well at 50 C with 2-(methylamino)- performed on glass plates precoated with silica gel
(
)
ethanol to derive 4m, which was an important intermediate of impregnated with a fluorescent indicator (254 nm). GC
1
5
rosiglitazone.
analyses were performed on an Agilent 7890A instrument
4
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(Column: Agilent 19091J-413: 30 m×320 μm×0.25 μm. H. FID. investigations. Electron-deficient fluoroarenes without nitro
detection). IR was taken on a Thermo Fisher Nicolet iS10 group and various electron-deficient chloroarenes were also
spectrometer. All NMR spectra were recorded on an AVANCE applied in the chemistry. These metal-free reactions take place
5
00 Bruker spectrometer operating at 500 MHz and 125 MHz in recyclable [Omim]Br under relatively mild conditions with
in CDCl , respectively, and chemical shifts were reported in high yields and broad substrate scope, thereby making it more
ppm. Elemental analyses were performed on a Yanagimoto environmentally friendly and suitable for large-scale
3
MT3CHN recorder.
operations, and offering considerable applications to complex
targets in organic and medicinal chemistry. Other
transformations in ILs are ongoing in our group.
N
General procedure for the S Ar in [Omim]Br: A mixture of aryl
halides 1.0 mmol, nucleophile (thiols, amines and arenols) 1.1
mmol and K PO 1.1 mmol was added in [Omim]Br (1 mL),
3
4
o
which was stirred at a certain temperature (rt to 120 C) for 6
h to 24 h. Upon completion, the reaction mixture was
extracted by methyl tert-butyl ether (MTBE) (3×2 mL). The
organic phase was collected and filtered through a bed of silica
gel layered over Celite. The volatiles were removed in vacuo to
afford the crude product. Further column chromatography on
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
China (21402093) and Jiangsu (BK20140776), Chinese
Postdoctoral Science Foundation (2016T90465, 2015M571761)
and Fundamental Research Funds for the Central Universities
(
30915011315) for financial support.
silica gel was needed to afford the pure product (3-5)
The synthesis of 6: A mixture of 1,4-difluoro-2-nitrobenzene
.0 mmol, (3,4-dimethoxyphenyl)methanethiol 1.1 mmol, Notes and references
.
1
K
3
PO
stirred at 50 C for 12 h. After reaction completed, Zn dust (4.0
equiv) and NH Cl (4.0 equiv) were weighted to the mixture.
4
1.1 mmol was added in [Omim]Br (1.0 mL), which was
1
2
(a) R. D. Rogers and K. R. Seddon, Science, 2003, 302, 792; (b)
V. I. Pârvulescu and C. Hardacre, Chem. Rev., 2007, 107, 2615;
(c) M. Armand, F. Endres, D. R. MacFarlane, H. Ohno and B.
o
4
Scrosati, Nat. Mater., 2009, 8, 621; (d) A. S. Amarasekara,
The solution was vigorously stirred at room temperature
overnight (18 h). Upon completion, the reaction mixture was
extracted by methyl tert-butyl ether (MTBE) (3×2 mL). The
organic phase was collected and filtered through a bed of silica
gel layered over Celite. The volatiles were removed in vacuo to
afford the crude product. Further column chromatography on
Chem. Rev., 2016, 116, 6133; (e) P. C. Marr and A. C. Marr,
Green Chem., 2016, 18, 105.
(a) N. V. Plechkova and K. R. Seddon, Chem. Soc. Rev., 2008,
37, 123; (b) K. L. Luska, P. Migowski and W. Leitner, Green
Chem., 2015, 17, 3195; (c) P. Lozano, J. M. Bernal, E. Garcia-
Verdugo, G. Sanchez-Gomez, M. Vaultier, M. I. Burguete and
S. V. Luis, Green Chem., 2015, 17, 3706.
silica gel was needed to afford the pure product
The synthesis of 7: A mixture of 2,4,6-trichloropyrimidine 1.0
mmol, morpholine 2.2 equiv and K PO 1.1 mmol was added in
Omim]Br (1.0 mL), which was stirred at rt for 12 h. Upon
6.
3
4
(a) R. Hayes, G. G. Warr and R. Atkin, Chem. Rev., 2015, 115,
357; (b) P. A. Hunt, C. R. Ashworth and R. P. Matthews,
Chem. Soc. Rev., 2015, 44, 1257; (c) R. Lungwitz and S.
Spange, New J. Chem., 2008, 32, 392.
6
3
4
[
(a) P. I. Dalko and L. Moisan, Angew. Chem. Int. Ed., 2004, 43,
138; (b) A. Sarkar, S. R. Roy and A. K. Chakraborti, Chem.
completion, the reaction mixture was extracted by methyl tert-
butyl ether (MTBE) (3×2 mL). The organic phase was collected
and filtered through a bed of silica gel layered over Celite. The
volatiles were removed in vacuo to afford the crude product.
Further column chromatography on silica gel was needed to
5
Commun., 2011, 47, 4538; (c) R. Kumar, Saima, A. Shard, N.
H. Andhare, Richa and A. K. Sinha, Angew. Chem. Int.Ed.
2
015, 54, 828.
5
6
(a) T. Terrier, In Modern Nucleophilic Aromatic Substitution,
Wiley-VCH: Weinheim, 2013; (b) E. Vitaku, D. T. Smith and J.
T. Njardarson, J. Med. Chem., 2014, 57, 10257; (c) M.
Baumann and I. R. Baxendale, Beilstein J. Org. Chem., 2013,
afforded the pure product 7.
The procedure of recycling [Omim]Br: After reaction
completion, the mixture was then extracted with MTBE (3×10
mL). The organic layer was collected and filtered through a bed
of silica gel layered over Celite. The volatiles were removed in
vacuo to afford the crude product 4m. To the phase of IL,
9
6
, 2265; (d) S. L. Gaonkar and H. Shimizu, Tetrahedron, 2010,
, 3314.
6
(a) X. Jia, L. Yu, J. Liu, Q. Xu, M. Sickert, L. Chen and M.
Lautens, Green Chem., 2014, 16, 3444; (b) C. P. Ashcroft, P. J.
Dunn, J. D. Hayler and A. S. Wells, Org. Process Res. Dev.,
2
015, 19, 740.
3 4
K PO 10.0 mmol was added, followed by 2-fluoropyridine 10.0
7
8
(a) T. Laird, Org. Process Res. Dev. 2012, 16, 1; (b) C. Jimenez-
Gonzales and D. J. Constable, In Green Chemistry and
Engineering: A Practical Approach, Wiley: New York, 2011.
(a) M. C. Bryan, B. Dillon, L. G. Hamann, G. J. Hughes, M. E.
Kopach, E. A. Peterson, M. Pourashraf, I. Raheem, P.
Richardson, D. Richter and H. F. Sneddon, J. Med. Chem.,
mmol and 2-(methylamino)ethanol 10.0 mmol at room
o
temperature and the reaction stirred for 24 h at 50 C. The
extraction cycle was then repeated for the separation of 4m
.
2
2
013, 56, 6007; (b) W. J. W. Watson, Green Chem., 2012, 14,
51.
Conclusions
9
1
(a) N. A. Isley, R. T. H. Linstadt, S. M. Kelly, F. Gallou and B. H.
Lipshutz, Org. Lett., 2015, 17, 4734; (b) G.-p. Lu and C. Cai,
RSC Adv., 2014, 4, 59990.
0 (a) M. Imoto, Y. Matsui, M. Takeda, A. Tamaki, H. Taniguchi,
K. Mizuno and H. Ikeda, J. Org. Chem., 2011, 76, 6356; (b) D.
N. Kommi, P. S. Jadhavar, D. Kumar and A. K. Chakraborti,
In summary, we disclose an efficient protocol for the
formation of Caryl-heteroatom (S, N, O) bonds through S Ar
N
reactions in [Omim]Br. The reaction can be promoted by an
electrophile-nucleophile dual activation which is mainly
triggered by HBs between IL and substrates based on further
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ARTICLE
Journal Name
Green Chem., 2013, 15, 798. (c) B. Tanwar, P. Purohit, B. N. 13 (a) G. L. Khatik, R. Kumar and A. K. Chakraborti, Org. Lett.,
Raju, D. Kumar, D. N. Kommi and A. K. Chakraborti, RSC Adv., 2006, , 2433; (b) A. K. Chakraborti, L. Sharma and M. K.
015, , 11873.
8
2
5
Nayak, J. Org. Chem., 2002, 67, 2541; (c) A. K. Chakraborti, S.
1
1 (a) P. T. Anastas and J. C. Warner, in Green Chemistry:
Theory and Practice, Oxford University Press: Oxford, UK,
Rudrawar, K. B. Jadhav, G. Kaur and S. V. Chankeshwara,
Green Chem., 2007, 9, 1335.
998; (b) P. T. Anastas and T. Williamson, in Green 14 The use of bases can also enhance the nucleophilicity of
1
Chemistry, Frontiers in Benign Chemical Synthesis and
thiols by capturing of their proton, which may be another
reason for that the proton shifted from 10.233 to 10.186.
G. Jessop, Green Chem., 2011, 13, 1391; (c) G.-p. Lu, C. Cai 15 (a) S. L. Gaonkar and H. Shimizu, Tetrahedron, 2010, 66, 3314;
Process, Oxford University of Press: Oxford, UK, 1998; (c) P.
and B. H. Lipshutz, Green Chem., 2013, 15, 105; (d) G.-p. Lu,
C. Cai, F. Chen, R.-l. Ye and B.-j. Zhou, ACS Sustain. Chem.
(b) D. V. Jawale, U. R. Pratap and R. A. Mane, Bioorg. Med.
Chem. Lett., 2012, 22, 924.
Eng., 2016,
2 M. J. Kamlet, J. L. M. Abboud, M. H. Abraham and R. W. Taft,
4
, 1804.
16 W. Zhu, Y. Liu, Y. Zhao, H. Wang, L. Tan, W. Fan and P. Gong,
Arch. Pharm., 2012, 345, 812.
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J. Org. Chem., 1983, 48, 2877.
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| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Aromatic nucleophilic substitution reaction in ionic liquid is promoted by an
electrophile-nucleophile dual activation

Green Chemistry
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Facile aromatic nucleophilic substitution reactions (S Ar) in
N
ionic liquid: An electrophile-nucleophile dual activation by
[Omim]Br for the reaction
Xiao Zhang, Guoꢀping Lu*, Chun Cai
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu
210094, P. R. China
*
Corresponding Author Eꢀmail: glu@njust.edu.cn
1
2
3
. Experimental
2
4
. Characterization Data
. NMR Spectra of All Products
17
1

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1
Experimental
1
General procedures for the synthesis of ionic liquids : NꢀMethylimidazole or
,2ꢀdimethylꢀimidazole 40 mmol, 1ꢀhaloalkane 48 mmol and ethyl acetate 10 mL
1
were heated under reflux for 24 h. The biphasic system obtained was separated and
the upper organic phase discharged. The bottom product phase was washed with ethyl
acetate (3 × 10 mL), and dried under vacuum to give 1ꢀoctylꢀ3ꢀmethylimidazolium
4
bromide as a colourless liquid. [Omim]OAc and [Omim]HSO are synthesized by
ꢀ
ꢀ
exchanging the bromide ion of [Omim]Br with AcO or HSO4 in acidꢀbase
neutralization with NaOAc and NaHSO respectively.
4
Experimental Procedure for IR Studies
Figure S1 IR spectrum of (a) [Omim]Br, (b) 1ꢀFluoroꢀ2ꢀnitrobenzene 1a, (d) the mixing of 1a
and [Omim]Br after 30 min.
2

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Figure S2 IR spectrum of (a) [Omim]Br, (c) 4ꢀTolyl mercaptan 2a, (e) the mixing of 2a and
Omim]Br after 30 min.
[
Figure S3 IR spectrum of (a) [Omim]Br. (f) the mixing of 1a and 2a in [Omim]Br after 30 min.
(
g) the mixing of 1a and 2a in [Omim]Br after 2 h.
3

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Table S1 The characteristic frequency of compounds in IR
characteristic frequency
chemical bond
compound
ꢀ1
1
170.0 cm
CꢀN stretching imidazole ring
ꢀ
1
1
2
461.2ꢀ1570.2 cm
skeleton vibration of imidazole ring
saturated CꢀH stretching vibration
CꢀH stretching vibration of imidazole ring
CꢀF stretching vibration of benzene
[Omim]Br
ꢀ1
853.6ꢀ2935.6 cm
ꢀ
1
3
1
072.0 cm
ꢀ
1
238.5 cm
1ꢀfluoroꢀ2ꢀnitrobenzene
ꢀ1
1
347.5ꢀ1525.8 cm
CꢀNO
2
stretching vibration of benzene
1a
4ꢀtolyl mercaptan
2a
ꢀ
1
6
28.1 cm
CꢀS stretching vibration of benzene
SꢀH stretching vibration
ꢀ
1
2
561.4 cm
Results and Conclusions:
(
(
(
1) The formation of HB between the Cꢀ2 hydrogen of [Omim]Br and F atom of 1a is
evidenced by the facts that νCꢀH of imidazole ring in [Omim]Br is shifted from
3072.0 to 3063.3 and νCꢀF of 1a is shifted from 1238.5 to 1240.9. (Figure S1)
2) The interaction between [Omim]Br and 2a is evidenced by the facts that νCꢀH of
imidazole ring in [Omim]Br is shifted from 3072.0 to 3062.8 and νCꢀS of 2a is
shifted from 628.1 to 619.0. (Figure S2)
3) The interaction between [Omim]Br and substrates (1a and 2a) is evidenced by the
facts that νCꢀH of imidazole ring in [Omim]Br is shifted from 3072.0 to 3078.7 (f)
and 3080.2 (g). (Figure S3)
2
Characterization Data
2
o
o
(
2ꢀNitrophenyl)(pꢀtolyl)sulfane 3a, yellow solid, mp: 87ꢀ88 C (lit. 89ꢀ90 C), yield 94%, 230.3
1
mg. H NMR (500 MHz, CDCl
3
) δ 2.43 (s, 3H), 6.85 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H),
1
3
7
.28ꢀ7.34 (m, 3H), 7.46 (d, J = 8.0 Hz, 2H), 8.22 (d, J = 8,5 Hz, 1H). C NMR (125 MHz, CDCl
3
)
δ 21.5, 124.8, 125.9, 127.4, 128.3, 131.0, 133.5, 136.1, 140.2, 140.6, 145.0. MS (ESI) m/z: 245.
3
o
1
5
ꢀNitroꢀ2ꢀ(pꢀtolylthio)aniline 3b, yellow solid, 111ꢀ113 C, yield 84%, 218.4 mg. H NMR (500
MHz, CDCl ) δ 2.33 (s, 3H), 4.49 (s, 2H), 7.12ꢀ7.17 (m, 4H), 7.32 (d, J = 8.5 Hz, 1H), 7.49 (d, J =
3
1
3
8
1
3
.5 Hz, 1H), 7.55 (s, 1H). C NMR (125 MHz, CDCl ) δ 21.3, 109.3, 113.1, 126.0, 129.5, 130.3,
30.5, 134.3, 137.9, 147.2, 148.6. MS (ESI) m/z: 260.
4

Green Chemistry
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4
o
o
(
2ꢀChloroꢀ6ꢀnitrophenyl)(pꢀtolyl)sulfane 3c, yellow solid, mp: 72ꢀ74 C (lit. 69ꢀ70 C), yield 89%,
1
2
48.3 mg. H NMR (500 MHz, CDCl
3
) δ 2.30 (s, 3H), 7.07 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.0 Hz,
13
2
H), 7.41 (t, J = 8.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H). C NMR (125
) δ 21.3, 122.3, 124.5, 127.7, 130.1, 130.3, 133.5, 136.0, 137.7, 141.5, 155.6. MS
ESI) m/z: 279.
MHz, CDCl
3
(
o
(
2ꢀFluoroꢀ4ꢀnitrophenyl)(pꢀtolyl)sulfane 3d, pale yellow solid, mp: 91ꢀ93 C, yield 97%, 255.1 mg.
1
H NMR (500 MHz, CDCl
d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H). C NMR (125 MHz,
) δ 21.5, 110.7ꢀ111.0 (d, J = 26 Hz, 1C), 119.7, 124.6, 127.4, 131.2, 135.6, 137.6, 140.8,
45.8, 156.4ꢀ158.4 (d, J = 248 Hz, 1C). MS (ESI) m/z: 263.0416. Anal. Calcd for C13 S:
C, 59.31%; H, 3.83%; N, 5.32%. Found: C, 59.17%; H, 4.12; N, 5.04%.
3
) δ 2.28 (s, 3H), 6.97 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 2H), 7.30
13
(
CDCl
3
1
H10FNO
2
2
o
o
(
4ꢀNitrophenyl)(pꢀtolyl)sulfane 3e, yellow solid, mp: 78ꢀ80 C (lit. 81.5 C), yield 90%, 220.5 mg.
1
H NMR (500 MHz, CDCl
3
) δ 2.42 (s, 3H), 7.13 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.44
1
3
(
d, J = 8.0 Hz, 2H), 8.04 (d, J = 13.5 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 21.5, 124.1, 126.3,
126.6, 131.0, 135.2, 140.4, 145.3, 149.5. MS (ESI) m/z: 245.
o
1
2
ꢀNitroꢀ5ꢀ(pꢀtolylthio)phenol 3f, yellow solid, 118ꢀ120 C, yield 78%, 203.6 mg. H NMR (500
MHz, CDCl ) δ 2.43 (s, 3H), 6.63ꢀ6.67 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H),
3
13
7
.92 (d, J = 8.5 Hz, 1H), 10.76 (s, 1H). C NMR (125 MHz, CDCl
25.6, 130.8, 131.0, 135.5, 140.7, 135.6, 155.5. MS (ESI) m/z: 261.0460. Anal. Calcd for
S: C, 59.76%; H, 4.24; N, 5.36%. Found: C, 59.45%; H, 4.62; N, 5.15%.
3
) δ 21.5, 115.0, 117.8, 125.3,
1
13 3
C H11NO
5
o
1
(
4ꢀMethylꢀ2ꢀnitrophenyl)(pꢀtolyl)sulfane 3g, yellow solid, 105ꢀ107 C, yield 75%, 194.3 mg. H
NMR (500 MHz, CDCl3) δ 2,27 (s, 3H), 2.34 (s, 3H), 6.66 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.0 Hz,
5

Page 13 of 71
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13
1
H), 7.19 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.95 (s, 1H). C NMR (125 MHz, CDCl
δ 20.6, 21.5, 125.9, 127.8, 128.3, 130.9, 134.7, 135.4, 135.9, 136.6, 140.3, 144.9. MS (ESI) m/z:
59.
3
)
2
6
o
1
Methyl 4ꢀ(pꢀtolylthio)benzoate 3h, white solid, mp: 101ꢀ103 C, yield 51%, 131.6 mg. H NMR
(
500 MHz, CDCl ) δ 2.39 (s, 3H), 3.88 (s, 3H),7.14 (d, J = 7.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H),
3
13
7
3
.40 (d, J = 8.5 Hz, 2H),7.87 (d, J = 8.0 Hz, 2H). C NMR (125 MHz, CDCl ) δ 21.4, 52.2, 126.8,
127.2, 128.3, 130.1, 130.6, 134.5, 139.3, 145.5, 166.9. MS (ESI) m/z: 258.
7
o
Phenyl(4ꢀ(pꢀtolylthio)phenyl)methanone 3i, pale yellow solid, 123ꢀ125 C, yield 76%, 231.0 mg.
1
H NMR (500 MHz, CDCl ) δ 2.40 (s, 3H), 7.18 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H),
3
1
3
7
.43ꢀ7.48 (m, 4H), 7.57 (t, J = 8.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H). C
3
NMR (125 MHz, CDCl ) δ 21.3, 126.5, 128.0, 128.3, 129.9, 130.6, 130.8, 132.3, 134.4, 134.5,
137.8, 139.3, 145.3, 195.8. MS (ESI) m/z: 304.
8
o
o
4
ꢀ(pꢀTolylthio)benzonitrile 3j, white solid, mp: 100ꢀ102 C (lit. 102ꢀ103 C), yield 83%, 186.8
1
mg. H NMR (500 MHz, CDCl
3
) δ 2.42 (s, 3H), 7.13 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H),
13
7
.43 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 21.4, 108.3,
118.9, 126.7, 126.8, 130.8, 132.3, 135.0, 140.0, 146.6. MS (ESI) m/z: 225.
9
o
o
1
7
7
ꢀ(4ꢀ(pꢀTolylthio)phenyl)ethanꢀ1ꢀone 3k, pale yellow solid, mp: 88ꢀ90 C (lit. 90ꢀ92 C), yield
1
6%, 183.9 mg. H NMR (500 MHz, CDCl
3
) δ 2.40 (s, 3H), 2.54 (s, 3H), 7.15 (d, J = 8.5 Hz, 2H),
1
3
.23 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H). C NMR (125 MHz,
) δ 21.4, 26.6, 126.8, 128.0, 129.0, 130.7, 134.3, 134.6, 139.5, 146.1, 197.3. MS (ESI) m/z:
CDCl
3
242.
1
0
1
2
2
=
ꢀ(pꢀTolylthio)pyridine 3l, pale yellow oil, yield 77%, 154.8 mg. H NMR (500 MHz, CDCl ) δ
3
.40 (s, 3H), 6.83 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.41 (t, J
1
3
7.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 8.41 (d, J = 5.0 Hz, 1H). C NMR (125 MHz, CDCl ) δ
3
21.5, 119.7, 121.0, 127.4, 130.6, 135.4, 136.7, 139.6, 149.6, 162.3. MS (ESI) m/z: 201.
6

Green Chemistry
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1
1
o
o
(
4ꢀBromophenyl)(4ꢀnitrophenyl)sulfane 3m, pale yellow solid, mp: 94ꢀ96 C (lit. 92ꢀ94 C),
1
yield 87%, 269.7 mg. H NMR (500 MHz, CDCl
3
) δ 7.19 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz,
13
2
H), 7.57 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 124.3,
127.2, 130.0, 133.4, 136.1, 145.8, 147.5. MS (ESI) m/z: 310.
9
o
1
(
4ꢀFluorophenyl)(4ꢀnitrophenyl)sulfane 3n, pale yellow solid, 82ꢀ84 C, yield 93%, 231.6 mg. H
1
3
NMR (500 MHz, CDCl
3
) δ 7.12ꢀ7.18 (m, 4H), 7.53ꢀ7.56 (m, 2H), 8.06 (d, J = 9.0 Hz, 2H).
) δ 117.6, 124.2, 125.6, 126.4, 137.3, 145.5, 148.6, 162.8ꢀ164.8 (d, J =
50 Hz, 1C). MS (ESI) m/z: 249.
C
NMR (125 MHz, CDCl
3
2
1
2
o
o
2
1
7
ꢀ((4ꢀNitrophenyl)thio)pyridine 3o, pale yellow solid, mp: 84ꢀ86 C (lit. 84ꢀ85 C), yield 77%,
1
78.6 mg. H NMR (500 MHz, CDCl
3
) δ 7.19 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H),
1
3
3
.59ꢀ7.65 (m, 3H), 8.18 (d, J = 9.0 Hz, 2H), 8.52 (d, J = 7.5 Hz, 1H). C NMR (125 MHz, CDCl )
δ 122.2, 124.3, 125.0, 132.0, 137.5, 142.5, 147.1, 150.6, 156.7. MS (ESI) m/z: 232.
1
3
o
o
2
1
ꢀ((4ꢀNitrophenyl)thio)pyrimidine 3p, yellow solid, mp: 108ꢀ110 C (lit. 108ꢀ113 C), yield 83%,
1
93.4 mg. H NMR (500 MHz, CDCl
3
) δ 7.07 (t, J = 7.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 8.24 (d,
1
3
J = 8.5 Hz, 2H), 8.52 (d, J = 7.5 Hz, 2H). C NMR (125 MHz, CDCl ) δ 118.1, 124.1, 134.9,
3
138.7, 148.0, 157.9, 170.9. MS (ESI) m/z: 233.
1
4
o
o
(
2ꢀNitrophenyl)(octadecyl)sulfane 3q, yellow solid, mp: 52ꢀ54 C (lit. 58ꢀ59 C), yield 91%,
1
3
70.4 mg. H NMR (500 MHz, CDCl
3) δ 0.87 (t, J = 7.0 Hz, 3H), 1.20ꢀ1.33 (m, 28H), 1.45ꢀ1.51
(
m, 2H), 1.70ꢀ1.76 (m, 2H), 2.94 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1
3
1
H), 7.54 (t, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ 14.3, 22.8,
28.0, 29.3 (2C), 29.5, 29.6, 29.7, 29.8, 32.1, 32.5, 124.3, 126.3, 126.7, 133.5, 138.5, 146.1. MS
(
ESI) m/z: 407.
1
5
1
Cyclohexyl(2ꢀnitrophenyl)sulfane 3r, yellow oil, yield 90%, 213.3 mg. H NMR (500 MHz,
7

Page 15 of 71
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DOI: 10.1039/C6GC01742H
CDCl
3
) δ 1.27ꢀ1.47 (m, 5H), 1.66 (d, J = 10.0 Hz, 1H), 1.80 (d, J = 10.0 Hz, 2H), 2.05 (d, J = 11.0
Hz, 2H), 3.27ꢀ3.31 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.45ꢀ7.52 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H).
13
3
C NMR (CDCl , 125 MHz) δ 25.8, 26.1, 32.7, 44.4, 124.9, 126.0, 128.5, 133.1, 136.0, 147.6.
MS (ESI) m/z: 237.
1
6
o
o
2
7
7
ꢀ((2ꢀNitrophenyl)thio)benzo[d]thiazole 3s, yellow solid, mp: 104ꢀ106 C (lit. 106 C), yield
1
4%, 213.1 mg. H NMR (500 MHz, CDCl
3
) δ 7.39ꢀ7.44 (m, 2H), 7.46ꢀ7.51 (m, 2H), 7.55 (t, J =
1
3
.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H). C NMR
(
125 MHz, CDCl ) δ 121.6, 123.8, 125.8, 126.4, 126.9, 127.6, 130.8, 133.3, 134.0, 137.7, 146.8,
3
153.8, 161.0. MS (ESI) m/z: 288.
1
7
o
o
Naphthalenꢀ2ꢀyl(2ꢀnitrophenyl)sulfane 3t, yellow solid, mp: 92ꢀ94 C (lit. 92ꢀ93 C), yield 82%,
1
2
7
8
1
30.4 mg. H NMR (500 MHz, CDCl
3
) δ 6.95 (d, J = 8.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H),
.31ꢀ7.36 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.62ꢀ7.67 (m, 2H), 7.82ꢀ7.98 (m, 3H), 8.22 (s, 1H),
13
.29 (d, J = 8.0 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ 125.2, 125.9, 127.2, 127.8, 128.0, 128.2,
28.3, 128.8, 130.1, 131.7, 133.6, 133.7, 134.1, 136.1, 139.5, 145.2. MS (ESI) m/z: 281.
1
8
1
Allyl(2ꢀnitrophenyl)sulfane 3u, light yellow oil, yield 74%, 144,3 mg. H NMR (500 MHz,
CDCl ) δ 3.65 (d, J = 6.5 Hz, 2H), 5.25 (d, J = 10.0 Hz, 1H), 5.37 (d, J = 16.5 Hz, 1H)，5.89ꢀ5.94
m, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H), 8.20 (t, J =
3
(
1
3
7
1
.5 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ 35.6, 119.5, 124.7, 126.0, 127.2, 131.8, 133.3, 137.1,
46.4. MS (ESI) m/z: 195.
19
1
(
2ꢀNitrophenyl)(nonyl)sulfane 3v, Light yellow oil, yield 71%, 385.8 mg. H NMR (500 MHz,
CDCl ) δ 2.44ꢀ2.55 (m, 2H), 3.22 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
3
1
3
1
H), 7.62ꢀ7.65 (m, 1H), 8.23ꢀ8.25 (m, 1H). C NMR (CDCl
3
, 125 MHz) δ 22.2, 29.3ꢀ29.7 (m),
1
9
1
24.6, 125.3, 125.6, 133.0, 134.5, 145.7. F NMR (CDCl , 470 MHz) δ ꢀ126.1, ꢀ123.3, ꢀ122.8,
3
ꢀ121.8, ꢀ114.2, ꢀ80.8. MS (ESI) m/z: 501.
8

Green Chemistry
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DOI: 10.1039/C6GC01742H
2
0
o
o
Benzyl(2ꢀnitrophenyl)sulfane 3w, yellow solid, mp: 82ꢀ84 C (lit. 82ꢀ83 C), yield 98%, 240.1
1
mg. H NMR (CDCl , 500 MHz) δ 4.20 (s, 2H), 7.25 (t, J = 7.0 Hz, 1H), 7.29 (t, J = 7.0 Hz, 1H),
3
7
8
1
.34 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H),
1
3
3
.20 (t, J = 8.0 Hz, 1H). C NMR (CDCl , 125 MHz) δ 37.7, 124.9, 126.2, 127.1, 127.9, 129.0,
29.2, 133.7, 135.1, 137.9, 146.0. MS (ESI) m/z: 245.
2
1
o
(
3,4ꢀDimethoxybenzyl)(4ꢀfluoroꢀ2ꢀnitrophenyl)sulfane 3x, Light yellow solid, mp: 92ꢀ94 C (lit.
o
1
9
2ꢀ94 C), yield 94%, 303.6 mg. H NMR (CDCl , 500 MHz) δ 3.97 (s, 6H), 4.25 (s, 2H), 6.91 (t,
3
J = 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 7.36ꢀ7.40 (m, 1H), 7.52ꢀ7.55 (m, 1H), 7.98ꢀ8.01 (m, 1H).
1
3
C NMR (CDCl
20.1, 120.2ꢀ120.4 (d, J = 25 Hz, 1C), 126.1, 128.3, 131.7, 145.7, 147.8, 148.3, 157.4ꢀ159.4 (d, J
248 Hz, 1C). MS (ESI) m/z: 323.
3
, 125 MHz) δ 37.0, 54.9 (2C), 110.3, 111.0, 112.0ꢀ112.2 (d, J = 26 Hz, 1C),
1
=
1
7
o
1
2
,5ꢀDichloroꢀ4ꢀ(pyrrolidinꢀ1ꢀyl)pyrimidine 4a, white solid, 78ꢀ80 C, yield 92%, 200.6 mg. H
1
3
3
3
NMR (500 MHz, CDCl ) δ 1.91 (s, 4H), 3.77 (s, 4H), 7.91 (s, 1H). C NMR (125 MHz, CDCl ) δ
25.4, 49.8, 112.4, 156.7, 157.3, 157.6. MS (ESI) m/z: 217.
2
2
1
2
,5ꢀDichloroꢀN,Nꢀdiethylpyrimidinꢀ4ꢀamine 4b, colorless oil, yield 81%, 177.4 mg. H NMR
13
(500 MHz, CDCl
3
) δ 1.22 (t, J = 8.0 Hz, 6H), 3.61ꢀ3.65 (m, 4H), 7.91 (s, 1H). C NMR (125
MHz, CDCl ) δ 13.7, 44.5, 112.2, 157.5, 157.9, 158.3. MS (ESI) m/z: 219.
3
23
o
o
1
2
ꢀNitroꢀNꢀphenylaniline 4c, red solid, mp: 70ꢀ72 C (lit. 75 C), yield 85%, 181.9 mg. H NMR
(
500 MHz, CDCl ) δ 6.68 (t, J = 9.0 Hz, 1H), 7.13ꢀ7.20 (m, 4H), 7.28 (t, J = 7.5 Hz, 1H), 7.33 (t, J
3
13
=
3
7.5 Hz, 2H), 8.12 (d, J = 9.0 Hz, 1H), 9.41 (s, 1H). C NMR (125 MHz, CDCl ) δ 116.2, 117.6,
124.5, 125.8, 126.8, 129.9, 133.4, 135.8, 138.9, 143.2. MS (ESI) m/z: 214.
9

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2
4
o
o
Nꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀnitroaniline 4d, red solid, mp: 88ꢀ90 C (lit. 89 C), yield 84%, 205.0
1
mg. H NMR (500 MHz, CDCl
3
) δ 3.84 (s, 3H), 6.71 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H),
7
9
1
.00 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 9.0 Hz, 2H), 7.32 (t, J = 7.0 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H),
13
3
.41 (s, 1H). C NMR (125 MHz, CDCl ) δ 55.7, 115.1, 115.9, 116.9, 126.7, 127.2, 131.3, 132.6,
35.9, 144.6, 158.1. MS (ESI) m/z: 244.
2
5
o
o
4
1
ꢀ(4ꢀNitrophenyl)morpholine 4e, yellow solid, mp: 147ꢀ149 C (lit. 149ꢀ150 C), yield 95%,
1
97.6 mg. H NMR (500 MHz, CDCl
3
) δ 3.36 (t, J = 5.0 Hz, 4H), 3.84 (t, J = 5.0 Hz, 4H), 6.81 (d,
1
3
J = 9.5 Hz, 2H), 8.10 (d, J = 9.5 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 47.2, 66.5, 112.7, 126.0,
139.1, 155.1. MS (ESI) m/z: 208.
2
6
o
o
1
NꢀBenzylꢀ4ꢀnitroaniline 4f, yellow solid, mp: 144ꢀ146 C (lit. 147 C), yield 89%, 202.9 mg. H
NMR (500 MHz, CDCl ) δ 4.43 (d, J = 5.5 Hz, 2H), 4.94 (s, 1H),6.57 (d, J = 9.0 Hz, 2H),
3
13
7
.30ꢀ7.39 (m, 5H), 8.07 (d, J = 9.0 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 47.8, 111.5, 126.5,
127.5, 128.0, 129.1, 137.5, 138.4, 153.2. MS (ESI) m/z: 228.
2
7
o
o
1
8
7
1
ꢀ(4ꢀNitrophenyl)ꢀ1Hꢀimidazole 4g, pale yellow solid, mp: 193ꢀ195 C (lit. 195ꢀ198 C), yield
1
9%, 168.2 mg. H NMR (500 MHz, CDCl
3
) δ 7.27 (s, 1H), 7.37 (s, 1H), 7.58 (d, J = 9.0 Hz, 2H),
1
3
.98 (s, 1H), 8.37 (d, J = 9.5 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 117.8, 121.2, 125.9, 131.8,
35.5, 142.1, 146.4. MS (ESI) m/z: 189.
2
8
o
o
4
9
6
ꢀ(2ꢀFluoroꢀ4ꢀnitrophenyl)morpholin 4h, yellow solid, mp: 110ꢀ112 C (lit. 112ꢀ113 C), yield
1
9%, 223.7 mg. H NMR (500 MHz, CDCl
3
) δ 3.25 (t, J = 9.5 Hz, 4H), 3.84 (t, J = 5.0 Hz, 4H),
1
3
.89 (t, J = 8.0 Hz, 1H), 7.84 (d, J = 10.5 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H). C NMR (125 MHz,
) δ 50.0, 66.7, 112.7, 117.0, 121.1, 140.8, 145.6, 152.2ꢀ154.2 (d, J = 248 Hz, 1C). MS (ESI)
m/z: 226.
CDCl
3
10

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2
9
o
o
Phenyl(4ꢀ(pyrrolidinꢀ1ꢀyl)phenyl)methanone 4i, pale yellow solid, mp: 134ꢀ136 C (lit. 138 C),
1
yield 67%, 168.2 mg. H NMR (500 MHz, CDCl
3
) δ 2.03 (t, J = 6.5 Hz, 4H), 3.37 (t, J = 6.5 Hz,
4
H), 6.53 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 7.51 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5
13
3
Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H). C NMR (125 MHz, CDCl ) δ 25.6, 47.7, 110.7, 124.3, 128.1,
129.5, 131.1, 133.1, 139.6, 151.0, 195.2. MS (ESI) m/z: 251.
30
o
1
2
,4ꢀDichloroꢀ6ꢀ(pyrrolidinꢀ1ꢀyl)pyrimidine 4j, white solid, 84ꢀ86 C, yield 72%, 156.2 mg. H
NMR (500 MHz, CDCl
3
) δ 1.91ꢀ1.97 (m, 2H), 2.01ꢀ20.6 (m, 2H), 3.29 (t, J = 7.0 Hz, 2H), 3.57 (t,
1
3
J = 6.5 Hz, 2H), 6.15 (s, 1H). C NMR (125 MHz, CDCl
3
) δ 24.8ꢀ25.5 (d, J = 86 Hz, 1C),
46.9ꢀ47.4 (d, J = 65 Hz, 1C), 100.5, 159.1, 159.6, 161.4. MS (ESI) m/z: 217.
3
1
o
1
4
,6ꢀDichloroꢀ2ꢀ(pyrrolidinꢀ1ꢀyl)pyrimidine 4j’, white solid, 87ꢀ89 C, yield 15%, 32.6 mg. H
13
NMR (500 MHz, CDCl ) δ 1.96ꢀ1.98 (m, 4H), 3.56 (t, J = 7.0 Hz, 4H), 6.49 (s, 1H). C NMR
3
(
125 MHz, CDCl ) δ 25.4, 47.2, 107.2, 159.4, 161.4. MS (ESI) m/z: 217.
3
3
2
o
o
4
ꢀChloroꢀ2,6ꢀdi(piperidinꢀ1ꢀyl)pyrimidine 4k, pale yellow solid, mp: 93ꢀ95 C (lit. 95ꢀ96 C),
1
yield 78%, 218.4 mg. H NMR (500 MHz, CDCl
3
) δ 1.52ꢀ1.58 (m, 8H), 1.59ꢀ1.64 (m, 4H), 3.50 (t,
1
3
J = 5.0 Hz, 4H), 3.69 (t, J = 5.0 Hz, 4H), 5.79 (s, 1H). C NMR (125 MHz, CDCl ) δ 24.8ꢀ25.0 (d,
3
J = 23 Hz, 1C), 25.6ꢀ25.9 (d, J = 35 Hz, 1C), 44.9ꢀ45.3 (d, J = 51 Hz, 1C), 90.2, 160.4, 161.1,
163.2. MS (ESI) m/z: 280.
11

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3
2
o
o
4
ꢀChloroꢀ2,6ꢀdi(pyrrolidinꢀ1ꢀyl)pyrimidine 4l, pale yellow solid, mp: 78ꢀ80 C (lit. 79ꢀ82 C),
1
yield 81%, 204.1 mg. H NMR (500 MHz, CDCl
3
) δ 1.88ꢀ1.94 (m, 8H), 3.52 (t, J = 7.0 Hz, 8H),
13
5
1
.63 (s, 1H). C NMR (125 MHz, CDCl
3
) δ 25.6, 46.3ꢀ46.6 (d, J = 41 Hz, 1C), 90.7, 159.0, 159.9,
61.4. MS (ESI) m/z: 252.
3
3
1
2
ꢀ(Methyl(pyridinꢀ2ꢀyl)amino)ethanꢀ1ꢀol 4m, pale yellow oil, yield 94%, 142.9 mg. H NMR
(
500 MHz, CDCl
Hz, 1H), 6.56 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 8.5 Hz, 1H), 8.03 (d, J = 6.5 Hz, 1H). C NMR (125
MHz, CDCl ) δ 38.0, 54.5, 63.1, 106.5, 112.4, 137.9, 147.2, 159.4. MS (ESI) m/z: 152.
3
) δ 3.05 (s, 3H), 3.69 (t, J = 5.5 Hz, 2H), 3.83 (t, J = 5.0 Hz, 2H), 6.52 (d, J = 8.5
13
3
3
4
o
o
2
ꢀ(2ꢀNitrophenoxy)naphthalene 5a, brown solid, mp: 55ꢀ57 C (lit. 58 C), yield 80%, 212 mg.
1
H NMR (500 MHz, CDCl
m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 7.88ꢀ7.93 (m, 2H), 8.03 (d, J = 8.0 Hz, 1H). C NMR (125
MHz, CDCl ) δ 115.2, 119.8, 120.9, 123.5, 125.5, 126.0, 127.0, 127.4, 128.0, 130.5, 130.9, 134.3,
34.4, 141.6, 150.8, 153.7. MS (ESI) m/z: 265.
3
) δ 7.10 (d, J = 8.5 Hz, 1H), 7.25ꢀ7.33 (m, 2H), 7.42 (s, 1H), 7.47ꢀ7.56
13
(
3
1
3
5
o
1
6
ꢀ(4ꢀNitrophenoxy)quinoline 5b, red solid, 69ꢀ71 C, yield 78%, 207.5 mg. H NMR (500 MHz,
CDCl
3
) δ 7.08 (d, J = 9.0 Hz, 2H), 7.42ꢀ7.49 (m, 3H), 8.09 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 9.0 Hz,
13
2H), 8.22 (d, J = 9.0 Hz, 1H), 8.90 (s, 1H). C NMR (125 MHz, CDCl
3
) δ 116.4, 117.9, 122.1,
123.8, 126.2, 129.2, 132.3, 135.6, 143.3, 146.0, 150.3, 152.9, 162.9. MS (ESI) m/z: 266.
3
6
o
o
1
2
,4ꢀBis(2ꢀnitrophenoxy)benzene 5c, brown solid, mp: 158ꢀ160 C (lit. 159ꢀ160 C), yield 71%,
1
49.9 mg. H NMR (500 MHz, CDCl
3
) δ 7.03 (d, J = 8.0 Hz, 2H), 7.08 (s, 4H), 7.22 (t, J = 7.5 Hz,
12

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13
2
H), 7.53 (t, J = 8.0 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 120.4,
120.9, 123.5, 125.9, 134.4, 141.4, 150.8, 152.4. MS (ESI) m/z: 352.
(
8R,9S,13S,14S)ꢀ13ꢀMethylꢀ3ꢀ(2ꢀnitrophenoxy)ꢀ6,7,8,9,11,12,13,14,15,16ꢀdecahydroꢀ17Hꢀcyclop
37
o
1
enta[a]phenanthrenꢀ17ꢀone 5d, yellow solid, >250 C, yield 77%, 301.1 mg. H NMR (500 MHz,
CDCl ) δ 0.93 (s, 3H), 1.49ꢀ1.64 (m, 7H), 1.96ꢀ2.17 (m, 3H), 2.27ꢀ2.31 (m, 1H), 2.39ꢀ2.42 (m,
H), 2.49ꢀ2.54 (m, 1H), 2.88ꢀ2.90 (m, 2H), 6.79 (s, 1H), 6.82 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 8.5
Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.94 (d, J =
3
1
13
8
.5 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ 14.0, 21.7, 26.0, 26.5, 29.6, 31.7, 36.0, 38.3, 44.2,
48.1, 50.6, 60.5, 116.6, 119.4, 120.5, 122.9, 125.8, 127.0, 134.1, 136.3, 138.8, 141.4, 151.1, 153.8.
MS (ESI) m/z: 391.
38
1
1
ꢀNitroꢀ2ꢀ(pꢀtolyloxy)benzene 5e, yellow oil, yield 92%, 197.8 mg. H NMR (500 MHz, CDCl
3)
δ 7.01 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 7.16ꢀ7.20 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H),
13
7
.49 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ 119.9, 120.6,
123.3, 124.7, 125.9, 130.2, 134.3, 141.5, 150.9, 155.9. MS (ESI) m/z: 215.
3
9
o
o
1
1
9
6
ꢀNitroꢀ4ꢀphenethoxybenzene 5f, pale yellow solid, mp: 54ꢀ56 C (lit. 56ꢀ57 C), yield 79%,
1
92.0 mg. H NMR (500 MHz, CDCl
3
) δ 3.15 (t, J = 7.0 Hz, 2H), 4.26ꢀ4.30 (m, 2H), 6.94 (d, J =
13
.0 Hz, 2H), 7.22ꢀ7.36 (m, 5H), 8.18 (d, J = 9.5 Hz, 2H). C NMR (125 MHz, CDCl ) δ 35.6,
3
9.6, 114.6, 126.0, 126.9, 128.8, 129.1, 137.6, 141.6, 164.0. MS (ESI) m/z: 243.
3
8
o
o
1
ꢀ(4ꢀ(4ꢀMethoxyphenoxy)phenyl)ethanꢀ1ꢀone 5g, pale yellow solid, mp: 60ꢀ62 C (lit. 60ꢀ61 C),
1
yield 76%, 183.9 mg. H NMR (500 MHz, CDCl
3) δ 2.55(s, 3H), 3.82 (s, 3H), 6.92 (t, J = 7.5 Hz,
13
4
H), 7.01 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ 26.5, 55.8,
115.2, 116.5, 121.8, 130.7, 131.5, 148.6, 156.8, 163.1, 196.9. MS (ESI) m/z: 242.
13

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40
1
2
ꢀ((3,4ꢀDimethoxybenzyl)thio)ꢀ5ꢀfluoroaniline 6, light yellow oil, yield 92%, 269.6 mg. H
NMR (CDCl , 500 MHz) δ 3.72 (s, 3H), 3.74 (s, 2H), 3.79 (s, 3H), 4.44 (s, 2H), 6.27ꢀ6.34 (m, 1H),
3
6
.35ꢀ6.36 (m, 1H), 6.53 (d, J = 1.5 Hz, 1H), 6.61ꢀ6.62 (m, 1H), 6.69 (d, J = 8.0 Hz, 1H), 7.07ꢀ7.10
1
3
(
m, 1H). C NMR (CDCl
3
, 125 MHz) δ 38.2, 54.3, 54.5, 99.8ꢀ100.0 (d, J = 25 Hz, 1C),
03.7ꢀ103.8 (d, J = 22 Hz, 1C), 109.8, 110.8ꢀ110.9 (d, J = 22 Hz, 1C), 119.8, 129.5, 137.3, 137.4,
46.8ꢀ147.3 (d, J = 65 Hz, 1C), 149.3ꢀ149.4 (d, J = 11 Hz, 1C), 162.0, 164.0. MS (ESI) m/z: 293.
1
1
3
0
o
o
4
,4'ꢀ(6ꢀChloropyrimidineꢀ2,4ꢀdiyl)dimorpholine 7, white solid, mp: 139ꢀ141 C (lit. 139ꢀ142 C),
1
yield 83%, 235.7 mg. H NMR (500 MHz, CDCl
3
) δ 3.50 (s, 4H), 3.68ꢀ3.72 (m, 12H), 5.82 (s, 1H).
1
3
C NMR (125 MHz, CDCl
ESI) m/z: 284.
3
) δ 44.4, 66.6ꢀ66.9 (d, J = 39 Hz, 1C), 91.2, 160.6, 160.9, 163.9. MS
(
[1] (a) Simon, L. D, Simon, W. R. David, J. C. Aqueousꢀbiphasic hydroformylation of alkenes
promoted by“weak” surfactants. Green Chemistry 2009, 11(5), 630ꢀ637. (b) Rather, M. A.; Rather,
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[
[
3] Commercial chemical, CAS number: 91955ꢀ35ꢀ0.
4] Commercial chemical, CAS number: 870241ꢀ04ꢀ7.
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9] K, S. S.; Amrutha, P.; Thankachan, A.; Maria, T.; Gopinathan, A., An efficient ironꢀcatalyzed
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[
Sꢀarylation of aryl and alkylthiols with aryl halides in the presence of water under aerobic
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10] Gogoi, P., Role of TBATB in nano indium oxide catalyzed CꢀS bond formation. Scientific
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[
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NickelꢀCatalyzed CꢀS Bond Formation: Synthesis of Aryl Sulfides from Arylsulfonyl Hydrazides
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[
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[22] Commercial chemical, CAS number: 1531745ꢀ71ꢀ7.
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NMR Spectra of All Products
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H NMR of 3a
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C NMR of 3a
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H NMR of 3b
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C NMR of 3b
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H NMR of 3c
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C NMR of 3c
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H NMR of 3d
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C NMR of 3d
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H NMR of 3e
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C NMR of 3e
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H NMR of 3f
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C NMR of 3f
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